Polymorphic forms and process

ABSTRACT

This polymorph is particularly suitable in treating IPF by pulmonary administration.

TECHNICAL FIELD

The present invention relates to a polymorph of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.

BACKGROUND ART

Idiopathic pulmonary fibrosis (IPF) represents a massive worldwidehealth burden. It is a chronic condition of unknown etiology in whichrepeated acute lung injury causes progressive fibrosis resulting indestruction of lung architecture, deteriorating lung function withconsequent respiratory failure and death. Although idiopathic pulmonaryfibrosis (IPF) is the archetypal and most common cause of lung fibrosis,numerous respiratory diseases can progress to pulmonary fibrosis, andthis usually signifies a worse prognosis. The median time to death fromdiagnosis is 2.5 years and the incidence and prevalence of IPF continuesto rise. It remains one of the few respiratory conditions for whichthere are no effective therapies, and there are no reliable biomarkersto predict disease progression. The mechanisms resulting in pulmonaryfibrosis are unclear but centre around aberrant wound healing as aconsequence of repetitive epithelial injury from an as yet unknowncause. IPF is characterized by fibroblastic foci containingfibroblasts/myofibroblasts which show increased activation response tofibrogenic cytokines such as transforming growth factor-β1 (TGF-β1).There is a big unmet need for drugs for treatment of Idiopathicpulmonary fibrosis.

SUMMARY OF THE DISCLOSURE

3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideis a white to off white crystalline solid where 6 polymorphs as well asan amorphous form have been identified.

In one aspect, the present invention relates to a polymorph of acompound of formula (I)

The compound of formula (I) is3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic Form 1 as identified in the XRPD diffractogrampeak list

No. Pos. [° 2Th.] Rel. Int. [%] 1 7.1269 77.72 2 7.5067 56 3 10.12536.86 4 14.3791 32.28 5 15.0846 18.59 6 15.8201 35.78 7 16.7088 78.1 818.6001 21.29 9 19.7777 100 10 20.3353 57.04 11 21.7744 79.92 12 22.605335.8 13 23.4305 45.78 14 24.3658 51.03 15 25.8091 54.36 16 26.7046 25.3817 29.028 16.19 18 30.2989 28.02 19 32.2693 14.86 20 33.5132 11.55 2134.6078 11.54 22 35.8435 9.6 23 44.6257 22.73Moreover, the polymorphic form 1 of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidecan be identified in the XRPD diffractogram in FIG. 1 or FIG. 2.

In a further aspect of the present invention a polymorph of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideis designated Form 1 and is a hydrated crystalline form. The hydrate isnot stoichiometric but rather a channel hydrate. Form 1 is dried uponsynthesis, however it will pick up moisture and equilibrate at around3-5% water content. Form 1 is stable and does not convert to the otherforms over time. Furthermore, form 1 can be further processed bymicronization, which is particularly useful when preparing a compositionfor use in dry powder delivery to the lungs, in particular the narrowestparts of the lung tissue that is the bronchioles and the alveoli.

In a further aspect, the present invention relates to a pharmaceuticalcomposition comprising a polymorph of the present invention, andoptionally a pharmaceutically acceptable additive.

In a still further aspect the present invention relates to a process ofmaking a polymorph of the present invention comprising the steps ofsuspending or dissolving3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidein an organic solvent and then making form 1 by temperature cycling,crash cooling or evaporation, or a combination thereof.

In a further aspect, the present invention relates to a process forpreparing an amorphous form of a compound of formula (I)

comprising the steps of spray drying a solution of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidein an organic solvent and collecting the amorphous compound of formula(I).

In a still further aspect the present invention relates to a method fortreatment of pulmonary fibrosis in a human comprising administering tothe narrowest parts of the lung tissue of the human an amount of apolymorph of the present invention effective to treat said pulmonaryfibrosis.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: XRPD Diffractogram for Form 1.

FIG. 2: XRPD Diffractogram for Form 1.

FIG. 3: XRPD Diffractogram for Form 2.

FIG. 4: XRPD Diffractogram for Form 3.

FIG. 5: XRPD Diffractogram for Form 4.

FIG. 6: XRPD Diffractogram for Form 5.

FIG. 7: XRPD Diffractogram for Form 6.

FIG. 8: XRPD Diffractogram for micronized form 1.

FIG. 9: XRPD Diffractogram for micronized form 1.

FIG. 10: XRPD Diffractogram for micronized form 1.

DETAILED DESCRIPTION

The compound of formula (I) has the chemical name (IUPAC)3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.

The compound of formula (I) may be prepared as described inUS2014/0121179 or WO2014/067986, wherein an amorphous solid is produced.

The present invention concerns a polymorph of a compound of formula (I)

In one embodiment, the compound of formula (1) is3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic form 1 as identified in the XRPD diffractogrampeak list

No. Pos. [° 2Th.] Rel. Int. [%] 1 7.1269 77.72 2 7.5067 56 3 10.12536.86 4 14.3791 32.28 5 15.0846 18.59 6 15.8201 35.78 7 16.7088 78.1 818.6001 21.29 9 19.7777 100 10 20.3353 57.04 11 21.7744 79.92 12 22.605335.8 13 23.4305 45.78 14 24.3658 51.03 15 25.8091 54.36 16 26.7046 25.3817 29.028 16.19 18 30.2989 28.02 19 32.2693 14.86 20 33.5132 11.55 2134.6078 11.54 22 35.8435 9.6 23 44.6257 22.73

The compound of formula (I) is3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic form 1 as identified in the XRPD diffractogramin FIG. 1.

The compound of formula (I) is3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic form 1 as identified in the XRPD diffractogramin FIG. 2.

In a further embodiment, the compound of formula (I) is3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideas a hydrate.

In a still further embodiment the3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidehydrate contains 3-5% water (weight %).

In a further embodiment, the compound of formula (I) is3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideselected from Form 2, 3, 4, 5 or 6 as identified in the XRPDdiffractogram in FIGS. 3-7, respectively. Form 5 (FIG. 6) isparticularly interesting as it is stable and suitable for use in anebulizer for pulmonary administration.

In a still further embodiment the polymorph is a dry powder, such asmicronized polymorph. Such as, micronized Form 1.

In a further embodiment, the polymorph, such as Form 1, is micronized toa size that can reach the narrowest parts of the lung tissue of thehuman, such as the bronchioles and the alveoli.

In a further aspect, the present invention relates to a polymorph of thepresent invention for use in a method for treatment of pulmonaryfibrosis in a human Preferably the polymorph for use in treatment ofpulmonary fibrosis is selected from Form 1 and 5, typically Form 1.

In a still further aspect the present invention relates to apharmaceutical composition comprising the polymorph of the presentinvention, and optionally a pharmaceutically acceptable additive.Typically, the polymorph used in the composition is Form 1 as a drypowder, such as micronized dry powder neat or mixed with an additive,such as lactose.

In a further aspect, the present invention relates to a DPI comprising apolymorph of the present invention, such as form 1. In an embodiment,the polymorph, such as Form 1, is micronized to a size that can reachthe narrowest parts of the lung tissue of the human, such as thebronchioles and the alveoli. In a further embodiment, the DPI comprisingthe polymorph of form 1 for use in a method for treatment of pulmonaryfibrosis in a human. In a still further embodiment the DPI is a singleor multiple dose DPI inhaler. In one particular embodiment, the drypowder inhaler is RS01 Monodose Dry Powder Inhaler (Plastiape).

Another aspect concerns a process of making a polymorph Form 1 of thepresent invention comprising the steps of suspending or dissolving3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidein an organic solvent and then making Form 1 by temperature cycling,crash cooling or evaporation, or a combination thereof. The compound3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideused as starting material may be amorphous or any crystalline form sincethe above process will generate Form 1. In a further embodiment, theorganic solvent is selected from methanol, ethanol, acetone,acetonitrile, toluene, tert-butylmethylether, hexane anddiisopropylether as well as mixtures thereof.

A further aspect concerns a process for preparing an amorphous form of acompound of formula (I)

comprising the steps of spray drying a solution of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidein an organic solvent and collecting the amorphous compound of formula(I). The compound3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideused as starting material may be any crystalline form since the aboveprocess will generate the amorphous form from the dissolved compound. Ina further embodiment the organic solvent is selected from a mixture ofacetone and water, such as acetone:water 50:50 to 80:20. In a stillfurther embodiment the dissolved compound is introduced in a dryingchamber at a feed concentration of from 0.5% to 20% by weigth, such asfrom 1-10% weight, such as from 2-7% weight, e.g. about 3.5% weight. Ina further embodiment, the drying chamber has a drying gas temperature atthe inlet of from 120-160° C., such as from 140-150° C., e.g. about 144°C. In a still further embodiment the drying chamber has a drying gastemperature at the outlet of from 60-90° C., such as from 70-80° C.,e.g. about 75° C. In a further embodiment drying time in the dryingchamber is from 30-120 minutes, such as from 45-75 minutes, e.g. about50 minutes.

In a still further aspect the present invention relates to a method fortreatment of pulmonary fibrosis in a human comprising administering tothe narrowest parts of the lung tissue of the human an amount of apolymorph of the present invention, such as Form 1 or 5, effective totreat said pulmonary fibrosis.

In a further embodiment, the pulmonary fibrosis is Idiopathic pulmonaryfibrosis (IPF).

In a further embodiment, the administration is carried out by a drypowder inhaler. Typically, a single or multiple dose DPI inhaler isused. In one particular embodiment, the dry powder inhaler is RS01Monodose Dry Powder Inhaler (Plastiape).

When a polymorph of the compound of formula (I), typically Form 1, isformulated as a dry powder it may be present in a suitable particle sizeselected from a mean mass aerodynamic diameter (MMAD) between 0.1 and 20μm, such as a MMAD between 0.5 and 10 μm, such as between 1 and 5 μm,typically between 2 and 3 μm. The selected ranges do not exclude thepresence of particles sizes outside these ranges, but the selectedranges are those that provide the desired effect as described herein.

In a still further embodiment the narrowest parts of the lung tissue arethe bronchioles and the alveoli.

In a further embodiment the once daily amount is from 0.15 mg to 50 mg,such as 0.15 mg to 0.50 mg, 0.50 mg to 0.75 mg, 0.75 mg to 1.25 mg, 1.25mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 mg to 2 mg, 2 mg to 2.25 mg, 2.25mg to 2.5 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3 mg, 3 mg to 5 mg, 5 mg to7 mg, 7 mg to 8 mg, 8 mg to 10 mg, 10 mg to 20 mg and 20 mg to 50 mg.The once daily amount form 1.5 mg to 20 mg result in a concentration ofthe active compound of formula (I) in BAL fluids or macrophages or bothof from 1 nM to 500 μM. In particular, the once daily amount form 1.5 mgto 20 mg result in a concentration of the active compound of formula (I)in BAL fluids or macrophages or both of from 1 nM to 100 μM. Morepreferred concentrations of from 10 nM to 10 μM or more preferred 100 nMto 1 μM can be provided with once daily amount from 1 mg to 10 mg, suchas from 1 mg to 3 mg or 3 mg to 10 mg, e.g. 1 mg to 3 mg. Otherpreferred concentrations of the active compound of formula (I) in BALfluids is from 10 nM to 10 μM, such as from 100 nM to 10 μM, typicallyfrom 500 nM to 10 μM, such as up to 4 μM. Other preferred concentrationsof the active compound of formula (I) in macrophages is from 1 μM to 500μM, such as from 10 μM to 250 μM, typically from 50 μM to 200 μM, suchas up to 100 μM.

In a still further embodiment the treatment is chronic treatment.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a condition, such asa disease or a disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relief the symptoms andcomplications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. The treatment is performed in a chronic way.The patient to be treated is a human subject diagnosed with pulmonaryfibrosis or other types of lung fibrosis.

The term “an amount effective to treat pulmonary fibrosis” of a compoundof formula (I) of the present invention as used herein means an amountsufficient to cure, alleviate or partially arrest the clinicalmanifestations of pulmonary fibrosis and its complications. Effectiveamounts for each purpose will depend on the severity of the disease orinjury as well as the weight and general state of the subject. It willbe understood that determining an appropriate dosage may be achievedusing routine experimentation, by constructing a matrix of values andtesting different points in the matrix, which is all within the ordinaryskills of a trained physician or veterinary.

As used herein “pharmaceutically acceptable additive” is intendedwithout limitation to include carriers, excipients, diluents, adjuvant,colorings, aroma, preservatives etc. that the skilled person wouldconsider using when formulating a compound of the present invention inorder to make a pharmaceutical composition.

The adjuvants, diluents, excipients and/or carriers that may be used inthe composition of the invention must be pharmaceutically acceptable inthe sense of being compatible with the compound of formula (I) and theother ingredients of the pharmaceutical composition, and not deleteriousto the recipient thereof. It is preferred that the compositions shallnot contain any material that may cause an adverse reaction, such as anallergic reaction. The adjuvants, diluents, excipients and carriers thatmay be used in the pharmaceutical composition of the invention are wellknown to a person within the art.

As mentioned above, the compositions and particularly pharmaceuticalcompositions as herein disclosed may, in addition to the compoundsherein disclosed, further comprise at least one pharmaceuticallyacceptable adjuvant, diluent, excipient and/or carrier. In oneembodiment the pharmaceutical composition contains neat compound offormula I. In some embodiments, the pharmaceutical compositions comprisefrom 1 to 99 weight % of said at least one pharmaceutically acceptableadjuvant, diluent, excipient and/or carrier and from 1 to 99 weight % ofa compound of formula I as herein disclosed. The combined amount of theactive ingredient and of the pharmaceutically acceptable adjuvant,diluent, excipient and/or carrier may not constitute more than 100% byweight (100% w/w) of the composition, particularly the pharmaceuticalcomposition. In accordance with the present invention the pharmaceuticalcomposition may consist of neat compound of formula I (that is 100% w/wcompound of formula I) or contain a 1-90% w/w, such as 2-20% w/w, forinstance a 3% w/w blend of the compound of formula I or a 10% w/w blendof the compound of formula I. Typically, the 3% w/w blend is apharmaceutical composition containing 3% w/w compound of formula I and97% w/w lactose carrier. Typically, the 10% w/w blend is apharmaceutical composition containing 10% w/w compound of formula I and90% w/w lactose carrier.

To the person skilled in the art it is well known that particles with amean mass aerodynamic diameter (MMAD) between 0.1 and 20 μm (micrometer) have an increased probability of depositing in the terminalbronchial and alveolar regions. This particle size range is ideal formany indications in pulmonary drug delivery, since a portion of thematerial will still deposit in the upper airways as well. (Cf.Controlled Pulmonary Drug Delivery, Smith and Hickey, Editors, Springer2011, chapter 13).

In accordance with Controlled Pulmonary Drug Delivery, Smith and Hickey,Editors, Springer 2011 in particular chapters 13, 14 and 15 the skilledperson will know how to formulate compounds, such as the compound offormula (I) for pulmonary drug delivery.

Dry powder inhalers (DPI), are well known for dispensing medicament tothe lungs of a patient. Preferred DPIs for use in the present inventionis a monodose dry powder inhaler from Plastiape (HQ, Osnago, Italy), inparticular the RS01 Monodose Dry Powder Inhaler.

Current DPI designs include pre-metered and device-metered inhalers,both of which can be driven by patient inspiration alone or withpower-assistance of some type. Pre-metered DPIs contain previouslymeasured doses or dose fractions in some type of units (e.g., single ormultiple presentations in blisters, capsules, or other cavities) thatare subsequently inserted into the device during manufacture or by thepatient before use. Thereafter, the dose may be inhaled directly fromthe pre-metered unit or it may be transferred to a chamber before beinginhaled by the patient. Device-metered DPIs have an internal reservoircontaining sufficient formulation for multiple doses that are metered bythe device itself during actuation by the patient. The wide array of DPIdesigns, many with characteristics unique to the design, will presentchallenges in developing information in support of an application.Regardless of the DPI design, the most crucial attributes are thereproducibility of the dose and particle size distribution. Maintainingthese qualities through the expiration dating period and ensuring thefunctionality of the device through its lifetime under patient-useconditions will probably present the most formidable challenge.

Pressurized Metered-Dose Inhalers (pMDI) may also be suitable deliverydevices for the present compound of formula (I) and are described inControlled Pulmonary Drug Delivery, Smith and Hickey, Editors, Springer2011, chapter 8.

Several types of non-aerosol, breath actuated dry powder inhalers havetherefore been provided. For example, U.S. Pat. No. 5,503,144 to Bacon,shows a breath-actuated dry-powder inhaler. The device includes a drypowder reservoir for containing a dry powdered medicament, a meteringchamber for removal of the powdered medicament from the reservoir indiscrete amounts, and an air inlet for entraining the removed powderedmedicament through a mouthpiece upon patient inhalation.

U.S. Pat. No. 5,458,135 discloses a method and apparatus for producingan aerosolized dose of a medicament for subsequent inhalation by apatient. The method comprises first dispersing a preselected amount ofthe medicament in a predetermined volume of gas, usually air. Thedispersion may be formed from a liquid or a dry powder. The methodrelies on flowing substantially the entire aerosolized dose into achamber that is initially filled with air and open through a mouthpieceto the ambient. After the aerosolized medicament, has been transferredto the chamber, the patient will inhale the entire dose in a singlebreath.

U.S. Pat. No. 6,065,472 discloses a powder inhalation device comprisinga housing containing a pharmacologically active compound, a conduit withan outlet extending into the housing through which a user can inhale tocreate an airflow through the conduit, a dosing unit for delivering adose of the compound to the conduit and baffles arranged within the saidconduit to aid disintegration of powder agglomerates entrained in saidairflow.

Regardless of whether an aerosol or non-aerosol inhaler is used, it isof utmost importance that particles of the dispensed dry powdermedicament be small enough to ensure the adequate penetration of themedicament into the bronchial region of a patient's lungs duringinhalation. However, because the dry powder medicament is composed ofvery small particles, and often provided in a composition including acarrier such as lactose, non-defined agglomerates or aggregates of themedicament form at random prior to being dispensed. It has thereforebeen found preferably to provide breath-actuated dry powder inhalerswith means for breaking down the agglomerates of medicament ormedicament and carrier before inhalation of the medicament.

Boehringer Ingelheim provided a new technology in 1997 named Raspimatwhich is a mechanical nebulizer of the soft mist inhaler type. Thismechanical nebulizer is operated by hand without any need for a gaspropellant and no need for electrical power. Another mechanicalnebulizer is a human powered nebulizer developed by a team fromMarquette University. This nebulizer can by operated by an electricalcompressor, but it is also suitable for simple mechanical pumps in orderto provide a mist into the lungs of patients. Further nebulizers of theelectrical type are ultrasonic nebulizers based on the vibrating meshtechnology developed by inter alia PARI, Respironics, Omron, Beurer,Aerogen, or ultrasonic nebulizers based on an electronic oscillator thatgenerate a high frequency ultrasonic wave developed by inter alia Omronand Beurer. A further electrical nebulizer is a jet nebulizer also knownas atomizers.

In a further embodiment, the nebulizer is selected from a mechanicalnebulizer, such as a soft mist inhaler or a human powered nebulizer. Inanother embodiment, the nebulizer is selected from an electricalnebulizer, such as a nebulizer based on ultrasonic vibrating meshtechnology, a jet nebulizer, or an ultrasonic wave nebulizer. Particularsuitable nebulizers are based on vibrating mesh technology such as eFlowfrom PARI. When treating pulmonary fibrosis, in particular IPF, it isimportant to obtain adequately high local concentrations of thetherapeutic in the narrowest parts of the lung tissue, including thebronchioles and the alveoli. Further, it is important that thetherapeutic obtains an adequate residence time at the site of action inthe lung tissue. However, cough is a central symptom for patients withpulmonary fibrosis and in particular IPF—a symptom that is likely to beaggravated if an irritant is introduced into the lung. However,delivering the compound using a nebulizer, such as an electronicnebulizer, is particularly beneficial, since it allows delivery of thecompound to the smallest compartments in the lung, without causing anyirritation in the lung. Such relevant nebulizer systems are described inpublished patent applications US20040089295, US20050056274,US20060054166, US20060097068, US20060102172, US20080060640,US20110155768, and US20120167877, all of which are incorporated hereinby reference. Other suitable nebulizers are Tyvaso inhalation systemfrom United Therapeutics, Allera nebulizer system from Gilead,Bronchitol inhaler from Pharmaxis, Diskhaler from GSK, jet andultrasonic nebulizers from Actelion and Profile Pharma.

Further embodiments of the process are described in the experimentalsection herein, and each individual process as well as each startingmaterial constitutes embodiments that may form part of embodiments.

The above embodiments should be seen as referring to any one of theaspects (such as ‘method for treatment’, ‘pharmaceutical composition’,‘compound for use as a medicament’, or ‘compound for use in a method’)described herein as well as any one of the embodiments described hereinunless it is specified that an embodiment relates to a certain aspect oraspects of the present invention.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference to the same extent asif each reference was individually and specifically indicated to beincorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

Any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

The terms “a” and “an” and “the” and similar referents as used in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless other-wise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. Unless otherwise stated, all exact valuesprovided herein are representative of corresponding approximate values(e.g., all exact exemplary values provided with respect to a particularfactor or measurement can be considered to also pro-vide a correspondingapproximate measurement, modified by “about,” where appropriate).

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise indicated. No language in the specification should beconstrued as indicating any element is essential to the practice of theinvention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The description herein of any aspect or embodiment of the inventionusing terms such as “comprising”, “having”, “including” or “containing”with reference to an element or elements is intended to provide supportfor a similar aspect or embodiment of the invention that “consists of”,“consists essentially of”, or “substantially comprises” that particularelement or elements, unless otherwise stated or clearly contradicted bycontext (e.g., a composition described herein as comprising a particularelement should be understood as also describing a composition consistingof that element, unless otherwise stated or clearly contradicted bycontext).

This invention includes all modifications and equivalents of the subjectmatter recited in the aspects or claims presented herein to the maximumextent permitted by applicable law.

The present invention is further illustrated by the following examplesthat, however, are not to be construed as limiting the scope ofprotection. The features disclosed in the foregoing description and inthe following examples may, both separately and in any combinationthereof, be material for realizing the invention in diverse formsthereof.

Experimental

The current process to manufacture polymorphic Form 1 of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside involves a final purification step with either trituration orcrystallization from ethanol to produce Form 1.

Form 1 of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidecan be prepared via trituration following the steps below:

-   -   Suspend crystalline or amorphous        3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-(3-D-galactopyranoside        in ethanol (3.6 vol).    -   Warm the suspension to 70° C.±5° C.    -   Stir the mixture for 30 min at 70° C.±5° C.    -   Allow the mixture to cool to 20° C.±5° C.    -   Filter and rinse with eight portions of ethanol (8×0.75 vol).    -   Draw air through the filter cake for a minimum of 15 min.    -   Dry the filter cake in vacuo at 70° C. with an air bleed to        provide purified        3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.

Form 1 of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidecan be prepared via crystallization following the steps below:

-   -   Combine crystalline or amorphous        3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside        with ethanol (3.5 vol) and water (1.5 vol).    -   Heat the mixture to 45-50° C. over 60 to 90 minutes.    -   Clarify the mixture through a 1 μm filter at 18-23° C.    -   Adjust the temperature to 30-40° C. (target 38° C.) and        concentration the mixture under reduced pressure to about 5 vol.    -   Add ethanol (10 vol) to the mixture at a temperature of        30-40° C. (target 38° C.).    -   Re-concentrate the mixture to about 5 vol.    -   Heat the mixture to 65-75° C. (target 70° C.) and stir for 30-40        minutes.    -   Cool the mixture to 18-23° C. (target 20° C.) over at least 90        minutes.    -   Stir the mixture for at least 45 minutes at 18-23° C. (target        20° C.).    -   Filter and wash the filter cake with ethanol at 18-23° C.        (target 20° C.).    -   Dry the filter cake at 18-23° C. to provide purified        3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.

A polymorph screen was conducted using Form 1 material generated viatrituration as the final purification step. The polymorph screen resultsindicated that there are 6 potential polymorphs for3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.Table 2 indicates conditions that generated each polymorph (Form 1-6).

-   -   Form 1 is a hydrated form and can be produced from temperature        cycling, crash cooling and evaporation experiments in 8        different solvents including methanol, ethanol, acetone,        acetonitrile, toluene, tert-butylmethylether, hexane and        diisopropylether.    -   Form 2 is a channel hydrate or hygroscopic form and can be        produced from temperature cycling, crash cooling, anti-solvent        addition and evaporation experiments in 7 different solvents        including acetone, acetone:water (20%), methylethyl ketone,        tetrahydrofuran, dichloromethane, dimethylformamide and        dimethylacetamide.    -   Form 3 is a solvate and can be produced from temperature        cycling, anti-solvent addition and evaporation in 9 different        solvents including dichloromethane, dimethylacetamide, ethyl        acetate, isopropyl acetate, methyl isobutyl ketone,        tertahydrofuran, acetone, acetone:water (20%) and        dimethylacetamide.    -   Form 4 is a solvate and can be produced from temperature cycling        in 2-propanol.    -   Form 5 is a hydrate and can be produced from temperature cycling        in dimethylsulfoxide, water, water:propylene glycol (75:25) and        water:PEG400:ethanol (65:25:10).    -   Form 6 is a hydrate/solvate and can be produced from temperature        cycling and evaporation experiments in dimethylformamide and        N-methyl-2-pyrrolidone.

3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideForm 5 has also been prepared via microfluidization (wet polishing)using water as an anti-solvent.

The amorphous form of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidehas been prepared through spray drying from a solution of acetone:water.

To compare in vitro performance of the different forms for use ininhalation products, an aerodynamic particle size determination (APSD)was performed via New Generation Impactor (NGI) for Form 5 materialproduced via microfluidization and the amorphous form produced via spraydrying. These were compared with the APSD obtained from micronized Form1 material. For each APSD test, 20 mg3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidewas filled into a size 3 HPMC capsule and actuated using a PlastiapeMonodose inhaler device. The NGI results are provided in Table 3 anddemonstrate that all three forms (Form 1, Form 5 and amorphous) haveacceptable in vitro aerosol performance with Fine Particle Fraction(FPF) above 60% and MMAD values in the respirable range.

TABLE 3 APSD Results for Form 1, Form 5 and Amorphous3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside Fine Fine - Mean MassGeometric Particle Particle Aerodynamic Standard Dose Fraction DiameterDeviation Form (FPD) (FPF) (MMAD) (GSD) Form 1 (micronized)  7.4 mg 77%2.6 μm 1.8 μm Form 5  7.7 mg 63% 2.3 μm 2.3 μm (microfluidization)Amorphous 11.8 mg 91% 1.7 μm 1.8 μm (Spray Drying)

Micronized Form 1 was placed on stability under ICH conditions and theresults in Table 3A demonstrate that Form 1 is stable both chemicallyand physically. There is no increase in impurities and both the particlesize and crystalline form remain unchanged.

TABLE 3A Stability Results for Micronized Form 1 6 Months 12 Months TestAcceptance Criteria Initial @ 40° C./75RH 25° C./60RH Appearance Whiteto off-white solid Conforms Conforms Conforms Assay 95.0-105.0% w/w ¹97.9% 97.2% 97.7% Specified DEX283 ≤1% (a/a) ND ND ND impuritiesDEX-IMP-284-A ≤1% (a/a) ND ND ND DEX-IMP-284-B ≤1% (a/a) 0.90% 0.89%0.89% DEX-IMP-284-C ≤1% (a/a) 0.03% 0.05% 0.04% Unspecified ≤1% each(a/a) 0.922RRT: 0.922RRT: 0.922RRT: impurities 0.12% 0.12% 0.12%1.057RRT: 1.057RRT: 1.057RRT: 0.08% 0.11% 0.10% 1.184RRT: 1.184RRT:1.184RRT: 0.34% 0.34% 0.34% Total Impurities ≤2.5% (a/a) 1.54% 1.57%1.54% Water Content Report result  4.2%  5.2%  4.4% Microbial LimitsTAMC: NMT 100 cfu/g <10 cfu/g <10 cfu/g <10 cfu/g TYMC: NMT 10 cfu/g <10cfu/g <10 cfu/g <10 cfu/g S.aureus: absent in 1 g absent/g absent/gabsent/g P.aeruginosa: absent in 1 g absent/g absent/g absent/gBile-tolerant gram-negative absent/g absent/g absent/g bacteria: absentin 1 g Polymorphism Report Form Form 1 Form 1 Form 1 6 Months 12 MonthsTest Acceptance Criteria Initial @ 40 C./75RH 25° C./60RH Particle Size:Report results D10 Results: D10 Results: D10 Results: D10 Results(Target: 0.56 μm 0.50 μm 0.51 μm D50 Results D50 ~21 μm D50 Results: D50Results: D50 Results: D90 Results D90 ≤5 μm) 2.37 μm 1.97 μm 1.84 μm D90Results: D90 Results: D90 Results: 5.09 μm 4.68 μm 4.29 μm

FIG. 8 shows XRPD scan at Initial time point.

FIG. 9 shows XRPD scan at 6 Months at 40° C./75RH.

FIG. 10 shows XRPD scan at 12 Months at 25° C./60RH.

EXAMPLES

Preparation of Form 1

3 mL of methanol was added to 300 mg of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 900 ul methanol was added to 100 mg3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between room temperature (RT) and 40° C. (4 hour cycles) forabout 6 or 7 days. The sample was filtered and allowed to dry at ambientfollowed by about 2 hours drying under vacuum.

Form 1 has been shown to have suitable characteristics that justifiesits use in a dry powder inhaler (DPI).

Preparation of Form 2

3 mL of acetone: water (20%) was added to 300 mg of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 300 ul acetone:water (20%) wasadded to 100 mg3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between RT and 40° C. (4 hour cycles) for about 6-7 days. Thesample was filtered and allowed to dry at ambient followed by about 2hours drying under vacuum.

Preparation of Form 3

2.5 mL of methyl isobutyl ketone (MIBK) was added to 300 mg of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 900 ul of MIBK was added to 100 mgof3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between RT and 40° C. (4 hour cycles) for about 6-7 days. Thesample was filtered and allowed to dry at ambient followed by about 2-3hours drying under vacuum.

Preparation of Form 4

2 mL of 2-propanol was added to 300 mg of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 500 ul of 2-propanol was added to100 mg3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between RT and 40° C. (4 hour cycles) for about 6-7 days. Thesample was filtered and allowed to dry at ambient followed by about 2-3hours drying under vacuum.

Preparation of Form 5

2.5 mL of water was added to 300 mg of3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 800 ul water was added to 100 mg3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between RT and 40° C. (4 hour cycles) for about 6-7 days. Thesample was filtered and allowed to dry at ambient followed by about 2-3hours drying under vacuum.

Form 5 can also be prepared by microfluidization to produce materialwith a particle size in the respirable range. 10 g of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) was suspended in 190 g water. The suspension wasprocessed using a Microfluidics High Pressure Homogenizer equipped witha 200 μm auxiliary processing module and a 100 μm interaction chamber.The unit was operated at a pressure of approximately 750 bar. As a finalstep, the material was spray dried to isolate the dried Form 5 material.

Form 5 is stable and is particularly suitable for administration by anebulizer.

Preparation of Form 6

1 mL of dimethylformamide (DMF) was added to 300 mg of3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) or alternately 200 ul DMF was added to 100 mg3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside(e.g. amorphous form) to form a slurry. The slurry was temperaturecycled between RT and 40° C. (4 hour cycles) for about 0.5-1 day. Thesample formed a solution and was allowed to evaporate. The sample wasdried for ca. 2 hours under vacuum. Alternately, once precipitation ofwas observed during the evaporation step, the sample was temperaturecycled for a further about 1 day and dried for about 1 day under vacuum.

Preparation of Amorphous

Table 4 provides an example of spray-drying conditions used to prepareamorphous3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside.Alternately, the spray-drying solvent can have other proportions ofacetone:water from 50:50 to 80:20.

TABLE 4 Spray-Drying Conditions for Amorphous3,3′-Dideoxy-3,3′-bis[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranoside (API) Acetone: WaterSolvent (50:50)-250 mL API 8.0 g Feed Concentration 3.5% wt/wt Relativesaturation of the drying gas at the 1.4/0.1% outlet of the dryingchamber Flowrate of feed to spray dryer 5 ml/min Rotameter 60 mm Dryinggas temperature at inlet to drying 144° C. chamber Drying gastemperature at outlet of drying 75° C. chamber Temperature at exit ofcondenser 5° C. Drying time 50 min

1-15. (canceled)
 16. A polymorph of a compound of formula (I)


17. The polymorph of claim 1 wherein the compound of formula (I) is3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic form 1 as identified in the XRPD diffractogrampeak list No. Pos. [° 2Th.] Rel. Int. [%] 1 7.1269 77.72 2 7.5067 56 310.125 36.86 4 14.3791 32.28 5 15.0846 18.59 6 15.8201 35.78 7 16.708878.1 8 18.6001 21.29 9 19.7777 100 10 20.3353 57.04 11 21.7744 79.92 1222.6053 35.8 13 23.4305 45.78 14 24.3658 51.03 15 25.8091 54.36 1626.7046 25.38 17 29.028 16.19 18 30.2989 28.02 19 32.2693 14.86 2033.5132 11.55 21 34.6078 11.54 22 35.8435 9.6 23 44.6257 22.73


18. The polymorph of claim 16 wherein the compound of formula (I) is3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideand has the polymorphic form 1 as identified in the XRPD diffractogramin FIG.
 1. 19. The polymorph of claim 16 wherein the compound of formula(I) is3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosideas a hydrate.
 20. The polymorph of claim 19 wherein the3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidehydrate contains 3-5% water (weight %).
 21. The polymorph of claim 16wherein the polymorph is micronized.
 22. The polymorph of claim 21wherein the polymorph is micronized to a size that can reach thebronchioles and/or the alveoli of the human.
 23. A pharmaceuticalcomposition comprising the polymorph of claim 16, and optionally apharmaceutically acceptable additive.
 24. A process of making apolymorph Form 1 of claim 16 comprising the steps of suspending ordissolving3,3′-Dideoxy-3,3′-bis-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1,1′-sulfanediyl-di-β-D-galactopyranosidein an organic solvent and then making Form 1 by temperature cycling,crash cooling, evaporation, or a combination thereof.
 25. A method fortreatment of pulmonary fibrosis in a human comprising administering tothe lung tissue of the human an amount of the polymorph of claim 16effective to treat said pulmonary fibrosis.
 26. The method of claim 16wherein the administration is carried out by a dry powder inhaler. 27.The method of claim 26 wherein the administration is carried out by amonodose dry powder inhaler.
 28. The method of claim 25 wherein thepolymorph is administered to the bronchioles and/or the alveoli of thehuman.
 29. The method of claim 25 wherein the amount is a once dailyamount from 0.15 mg to 50 mg.
 30. The method of claim 29, wherein theamount is a once daily amount selected from the group consisting of:0.15 mg to 0.50 mg, 0.50 mg to 0.75 mg, 0.75 mg to 1.25 mg, 1.25 mg to1.5 mg, 1,5 mg to 1.75 mg, 1.75 mg to 2 mg, 2 mg to 2.25 mg, 2.25 mg to2.5 mg, 2.5 mg to 2.75 mg, 2.75 mg to 3 mg, 3 mg to 5 mg, 5 mg to 7 mg,7 mg to 8 mg, 8 mg to 10 mg, 10 mg to 20 mg and 20 mg to 50 mg.
 31. Amethod for treatment of pulmonary fibrosis in a human comprisingadministering to the lung tissue of the human an amount of the polymorphof claim 17 effective to treat said pulmonary fibrosis.
 32. A method fortreatment of pulmonary fibrosis in a human comprising administering tothe lung tissue of the human an amount of the polymorph of claim 18effective to treat said pulmonary fibrosis.
 33. A method for treatmentof pulmonary fibrosis in a human comprising administering to the lungtissue of the human an amount of the polymorph of claim 19 effective totreat said pulmonary fibrosis.
 34. A method for treatment of pulmonaryfibrosis in a human comprising administering to the lung tissue of thehuman an amount of the polymorph of claim 20 effective to treat saidpulmonary fibrosis.
 35. A method for treatment of pulmonary fibrosis ina human comprising administering to the lung tissue of the human anamount of the polymorph of claim 21 effective to treat said pulmonaryfibrosis.